Alveolar lung development is molded by fluid distension of terminal airways and cellular deformation. The pathways and effector molecules that transduce these mechanical signals during lung development are not well understood. Our long-term objective is to identify the cellular and molecular mechanisms that underlie the physiologic and pathophysiologic effects of tissue stretch (mechanical deformation) on fetal lung development. We have determined that parathyroid hormone-related protein (PTHrP) is a stretch-inducible signal expressed by lung type II (Til) cells. PTHrP promotes fetal lung development, in part, by stimulating differentiation of mesenchymal cells into lipofibroblasts (LIFs). In turn, mature LIFs express growth factors and lipogenic proteins, including leptin, which stimulate Til cell surfactant phospholipid synthesis. Our preliminary studies indicate that mechanical forces interact at several points with this epithelial-mesenchymal maturational loop to promote alveolar differentiation. We also have determined that disruption or inhibition of PTHrP signaling, or of its downstream effectors, can interfere with alveolar function and cause differentiation of LIFs into myofibroblasts (MYFs), resulting in lung scarring. Based on these findings, we plan to demonstrate that PTHrP and "physiologic" mechanical deformation interact to promote lung mesenchymal cell differentiation along the LIF pathway. Conversely, we hypothesize that PTHrP depletion interference will lead to alveolar dysfunction and mesenchymal differentiation to the MYF phenotype. In Aim 1 of this proposal, we will define the interactions between PTHrP signaling and mechanical forces during development of the distal lung and determine the molecular mechanisms underlying PTHrP-inducible differentiation of mesenchymal cells into LIFs. In Aim 2, we will determine intracellular signaling pathways and paracrine effectors that mediate how PTHrP-stimulated LIF differentiation promotes Til cytodifferentiation. Understanding these mechanisms will enhance knowledge of normal alveolization and response to injury, and may lead to novel treatments for chronic lung disease in infants.